US7700586B2 - Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders - Google Patents

Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders Download PDF

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US7700586B2
US7700586B2 US10/489,029 US48902904A US7700586B2 US 7700586 B2 US7700586 B2 US 7700586B2 US 48902904 A US48902904 A US 48902904A US 7700586 B2 US7700586 B2 US 7700586B2
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piperazine
dimethylphenoxy
branched
hydrogen
nitrophenylsulfonyl
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US20050070582A1 (en
Inventor
Yingfu Li
Akihiko Watanabe
Timothy B. Lowinger
Kevin Bacon
Norihiro Kawamura
Takuya Shintani
Tetsuo Kikuchi
Toshiya Moriwaki
Klaus Urbahns
Keiko Fukushima
Noriko Nunami
Takashi Yoshino
Toshiki Murata
Megumi Yamauchi
Hiroko Yoshino
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Bayer Healthcare LLC
Axikin Pharmaceuticals Inc
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Axikin Pharmaceuticals Inc
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Assigned to BAYER HEALTHCARE AG reassignment BAYER HEALTHCARE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LOWINGER, TIMOTHY B., KIKUCHI, TETSUO, YAMAUCHI, MEGUMI, YOSHINO, HIROKO, YOSHINO, TAKASHI, WATANABE, AKIHIKO, KAWAMURA, NORIHIRO, FUKUSHIMA, KEIKO, MORIWAKI, TOSHIYA, BACON, KEVIN, MURATA, TOSHIKI, NUNAMI, NORIKO, SHINTANI, TAKUYA, URBAHNS, KLAUS, LI, YINGFU
Publication of US20050070582A1 publication Critical patent/US20050070582A1/en
Assigned to ACTIMIS PHARMACEUTICALS, INC. reassignment ACTIMIS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAYER HEALTHCARE AG
Assigned to BAYER HEALTHCARE AG reassignment BAYER HEALTHCARE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: URBAHNS, KLAUS, LY, TAI-WEI, TAKEKAWA, YUKI, SUGIMOTO, HIROMI, SHINTANI, TAKUYA, YOSHINO, TAKASHI, BACON, KEVIN
Assigned to AXIKIN PHARMACEUTICALS, INC. reassignment AXIKIN PHARMACEUTICALS, INC. CONFIRMATORY ASSIGNMENT Assignors: ACTIMIS PHARMACEUTICALS, INC.
Assigned to BAYER HEALTHCARE LLC reassignment BAYER HEALTHCARE LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAYER PHARMACEUTICALS CORPORATION
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    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a sulfonamide derivative which is useful as an active ingredient of pharmaceutical preparations.
  • the sulfonamide derivatives of the present invention have CCR3 (CC type chemokine receptor 3) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis and other inflammatory/immunological disorders.
  • CCR3 CC type chemokine receptor 3
  • Chemokines are chemotactic cytokines of which major functions are migration of inflammatory cells that express relevant chemokine receptors on their surfaces to sites of inflammation, and activation of inflammatory cells.
  • eotaxin is an 8.4 kDa (74 amino acid) polypeptide and binds with high affinity solely to the receptor CCR3.
  • eotaxin causes chemotaxis of inflammatory cells expressing CCR3 [Elsner J., Hochstetter R., Kimming D. and Kapp A.: Human eotaxin represents a potent activator of the respiratory burst of human eosinophils. Eur. J. Immunol., 26: 1919-1925, 1996.].
  • the chemokine receptor CCR3 is a G protein-coupled, seven transmembrane domain receptor (GPCR) which binds to known ligands, in addition to eotaxin, including eotaxin-2 (CCL24), RANTES (CCL5), MCP-3 (CCL7) and MCP-4 (CCL13).
  • GPCR G protein-coupled, seven transmembrane domain receptor
  • CCR3 is expressed on inflammatory cells relevant to the chronic asthma pathology.
  • Such inflammatory cells include Eosinophils [Sabroe I., Conroy D. M., Gerard N. P., Li Y., Collins P. D., Post T. W., Jose P. J., Williams T. J., Gerard C. J., Ponath P. D. J. Immunol.
  • basophils [Uguccioni M., Mackay C. R., Ochensberger B., Loetscher P., Rhis S., LaRosa G. J., Rao P., Ponath P. D., Baggiolini M., Dahinden C. A. J. Clin. Invest. 100: 1137-1143, 1997]
  • Th2 cells [Sallusto F., Mackay C. R., Lanzavecchia A. Science. 277: 2005-2007, 1997), alveolar macrophages [Park I. W., Koziel H., Hatch W., Li X., Du B., Groopman J. E. Am. J. Respir. Cell Mol. Biol.
  • mice showed decreased eosinophilia after antigen challenge [Rothenberg M. E., MacLean J. A., Pearlman E., Luster A. D. and Leder P. J. Exp. Med., 185: 785-790, 1997] and in IL5-/eotaxin-double knock-out mice there is no eosinophilia or AHR in response to antigen challenge [Foster P. S., Mould A. W., Yang M., Mackenzie J., Mattes J., Hogan S. P., Mahalingam S., Mckenzie A. N. J., Rothenberg M. E., Young I. G., Matthaei K.
  • CCR3 and related chemokine including eotaxin has been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis, and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and athero-sclerosis. It is also implicated that binding of CCR3 and related chemokine is an important factor of virus infections including HIV [(Marone G, de Paulis A, Florio G, Petraroli A, Rossi F, Triggiani M.: Int Arch Allergy Immunol 2001 June;125(2)/89-95), (Li Y et al.,: Blood 2001 Jun.
  • CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment of such inflammatory and immunoregulatory disorders and diseases.
  • WO 00/76514 and WO 00/76513 disclose cyclopentyl modulators of chemokine receptors including CCR3 activity represented by the general formula:
  • X′′, x, y, R 1, , R 2, , R 3, , R 4, , R 5, , R 6 , R 7 , and R 8 are defined in the application.
  • This invention is to provide novel sulfonamide derivatives shown by the following formula (I), its tautomeric and stereoisomeric form, and the salts thereof.
  • a 7 to 12 membered diazabicyclic ring stands for a saturated bicyclic ring system consisting of 5 to 10 carbon atoms and 1 to 2 nitrogen atoms, wherein said bicyclic ring system does not exhibit a spiro ring connection.
  • This invention is also to provide a method for treating or preventing a CCR3 related disorder or disease in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.
  • this invention is to provide a use of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof in the preparation of a medicament for treating or preventing a CCR3 related disorder or disease.
  • the compounds of the present invention antagonise CCR3, they are useful for treatment and prophylaxis of diseases as follows:
  • asthma wheezing a rhinitis
  • allergic diseases rhinitis
  • autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.
  • CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment and prophylaxis of such inflammatory and immunoregulatory disorders and diseases.
  • the compounds of the present invention are also useful for treatment and prophylaxis of diseases like virus infections including HIV, lung granuloma, and Alzheimer's diseases, since the diseases also relate to CCR3.
  • the compounds of formula (I) are those wherein:
  • the compounds of formula (I) are those wherein:
  • the compounds of formula (I) are those wherein:
  • the compounds of formula (I) are those wherein:
  • the compounds of formula (I-2) are those wherein:
  • the compounds of formula (I-2) are those wherein:
  • the compounds of formula (I-2) are those wherein
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • the compounds of formula (I-2) are those wherein;
  • the compounds of formula (I-2) are those wherein;
  • the preferable compounds of the present invention are as follows:
  • the compound of the formula (I) of the present invention can be prepared by combining various known methods.
  • one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in “Protective Groups in Organic Synthesis (3rd Edition)” by Greene and Wuts, John Wiley and Sons, New York 1999.
  • the compound represented by the general formula (I-a) can be prepared by the Reaction A or A′ below.
  • Compound 1 (wherein L and L′ are identical or different and represent leaving group, such as halogen atom e.g., fluorine, chlorine, bromine, or iodine atom; C 6-10 arylsulfonyloxy group e.g., benzenesulfonyloxy, or p-toluenesulfonyloxy, and C 1-4 alkylsulfonyloxy group, e.g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the like) and H—R 7 ′ can be reacted to obtain compound 2 in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; n
  • the reaction temperature is usually, but not limited to, about ⁇ 10° C. to 200° C., and preferably about 10° C. to 80° C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 hr to 24 hrs.
  • the reaction can be advantageously conducted in the presence of a base.
  • the examples of the base include an alkali metal hydride such as sodium hydride or potassium hydride; alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • Compound 3 (wherein L is identical or different and represent leaving group, such as halogen atom e.g., fluorine, chlorine, bromine, or iodine atom; C 6-10 arylsulfonyloxy group e.g., benzenesulfonyloxy, or p-toluenesulfonyloxy; and C 1-4 alkylsulfonyloxy group, e.g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the like, W represents nitro, halogen, thiol, C 1-6 alkyl sulfinyl, sulfinic acid, sulfinic acid, sulfonamide and the like) and HY′—X can be reacted to obtain compound 4 in a similar manner as that for the preparation of I-a from compound 2 and HY′—X.
  • leaving group such as halogen atom e.g.,
  • Compound 4 can be converted to compound 5 (wherein L′ is as defined above) by known method in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); organic acid such as acetic acid; inorganic acid such as HCl and H 2 SO 4 ; water and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethy
  • the reaction temperature is usually, but not limited to about ⁇ 10° C. to 200° C., and preferably about 10° C. to 80° C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • the compound (I-a) can be further reacted to modify R 7 ′, e.g. to deprotect, or to modify R 5 ′ to obtain the compound having amino, halogen, hydroxy, cyano, C 1-6 alkoxy or amide group.
  • the compound represented by the general formula (I-b) can be prepared by the Reaction B below.
  • Reaction B is especially advantageous when R 5 ′′ is Br.
  • compound 6 and sulfonic acid halide e.g., chlorosulfonic acid
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • two or more of the solvents selected from the listed above can be mixed and used.
  • the reaction temperature is usually, but not limited to, about ⁇ 10° C. to 200° C., and preferably about 10° C. to 80° C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • Compound 8 can be prepared from compound 7 in two steps; (step 1) the reaction with H—R 7 ′ and (step 2) deprotection of methoxy group. (step 1) The reaction of compound 7 and H—R 7 ′ can be performed in a similar manner as that for the preparation of compound 2 from compound 1 and H—R 7 ′.
  • Step 2 The successive deprotection of methoxy group to obtain B-3 can be done by the reaction with Lewis acid such as, for example, BBr 3 , in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone, and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone, and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and
  • the reaction temperature is usually, but not limited to about ⁇ 10° C. to 200° C., and preferably about 10° C. to 80° C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • compound 8 can be reacted with X-L′′ (wherein X is defined as above, L′′ represents leaving group, such as boronic acid, halogen atom e.g., fluorine, chlorine, bromine, or iodine atom) to obtain the compound (I-b).
  • L′′ represents leaving group, such as boronic acid, halogen atom e.g., fluorine, chlorine, bromine, or iodine atom
  • the reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others.
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
  • ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF)
  • the reaction temperature is usually, but not limited to about ⁇ 10° C. to 200° C., and preferably about 10° C. to 100° C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • the reaction can be carried out in the presence of a catalyst, including for instance, cooper salts such as cooper(II) acetate, palladium salts such as palladium (II) acetate, and others.
  • the reaction can be advantageously conducted in the presence of a base.
  • the examples of the base include an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as cesium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide
  • alkali metal hydroxide such as sodium hydroxide and potassium hydroxide
  • carbonates such as cesium carbonate, sodium carbonate and potassium carbonate
  • alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate
  • organic amines such as pyridine, triethylamine and N,N-diisopropylethyl
  • the compound (I-b) can be farther reacted to modify R 7 ′, e.g. to deprotect, or to modify R 5 ′′ to obtain the compound having amino, halogen, hydroxy, cyano, C 1-6 alkoxy or amide group.
  • the compound (I-c) below can be advantageously prepared by the Reaction C below.
  • compound 8 which can be prepared as described in the Reaction B can be reacted with either trifluoromethanesulfonic anhydride or trifluoromethanesulfonic chloride to obtain compound 9.
  • the reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others.
  • two or more of the solvents selected from the listed above can be mixed and
  • the reaction temperature is usually, but not limited to about ⁇ 10° C. to 200° C., and preferably about 0° C. to 100° C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • the reaction can be advantageously conducted in the presence of a base.
  • the examples of the base include organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • compound 9 and HY′′—X can be reacted to obtain compound (I-c) in a similar manner as that for I-a from compound 2 and HY′—X.
  • the compound (I-c) can be further reacted to modify R 7 ′, e.g. to deprotect, or to modif R 5 ′′ to obtain the compound having amino, halogen, hydroxy, cyano, C 1-6 alkoxy or amide group.
  • the compound (I-d) below can be prepared by the Reaction D below.
  • the sulfoxide compounds of the formula (I-d′) can be prepared by oxidation of compound (I-a′) using appropriate oxidant including but not limited to, peroxide, such as hydrogen peroxide, t-butyl peroxide; peracids such as meta-chloroperbenzoic acid and the like.
  • peroxide such as hydrogen peroxide, t-butyl peroxide
  • peracids such as meta-chloroperbenzoic acid and the like.
  • the reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone, and others.
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • nitriles such as acetonitrile
  • amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone, and others.
  • DMF N,N-dimethylformamide
  • N-methylpyrrolidone
  • the reaction temperature is usually, but not limited to about ⁇ 10° C. to 200° C., and preferably about 0° C. to 100° C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • the sulfone compounds of the formula (I-d′′) can be prepared by oxidation of compound (I-a′) with an oxidant such as, for example, sodium periodate (NaIO 4 ) or sodium hypochlorite (NaOCl) in the presence of catalyst such as, for instance, ruthenium (III) chloride.
  • an oxidant such as, for example, sodium periodate (NaIO 4 ) or sodium hypochlorite (NaOCl) in the presence of catalyst such as, for instance, ruthenium (III) chloride.
  • the reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; water and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; water and
  • the sulfone compounds of the formula (I-d′′) can also be prepared by oxidation of compound (I-d′) in a similar manner as that for the oxidation of compound (I-a′).
  • the compound (I-d′) and (I-d′′) can be further reacted to modify R 7 ′, e.g., to deprotect, or to modify R 5 ′ to obtain the compound having amino, halogen, hydroxy, cyano, C 1-6 alkoxy or amide group.
  • Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.
  • Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like
  • organic acids such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like.
  • inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.
  • the compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts.
  • the compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
  • the dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.
  • the compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients.
  • Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
  • compositions of the present invention are pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically-acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefore.
  • the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container.
  • the carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • a diluent which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate,
  • the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets.
  • the powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention.
  • Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.
  • Sterile liquid formulations include suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
  • the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
  • a suitable organic solvent for example, aqueous propylene glycol.
  • Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in suitable oil.
  • the formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals.
  • a unit dosage form can be a capsule or tablets, or a number of capsules or tablets.
  • a “unit dose” is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients.
  • the quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.
  • Typical oral dosages of the present invention when used for the indicated effects, will range from about 0.01 mg/kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day.
  • parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to 100 mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
  • Human eosinophils were purified from peripheral blood. Twenty five ml of heparinized blood was layered on 15 ml of Mono-Poly Resolving Medium (#16-980-49DN, ICN Biomedicals Co. Ltd, Japan) in 50 ml tube (#2335-050, Iwaki, Japan) gently and then centrifuged at 400G, for 20 min, at room temperature. After centrifugation, red blood cells were removed by hypotonic lysis. The polymorphonuclear leukocyte pellet was incubated with anti-human CD16 Microbeads (#130-045-701, Milteynyi Biotec GmbH, Germany) for 30 min at 4° C.
  • Chemotaxis assay with the use of the obtained eosinophils was done by the same protocols as that using CCR3 stable transformants, L1.2 cells.
  • the animals used in this study were wild caught, adult male cynomolgus monkeys ( Macaca fascicularis ) weighing 4.0 to 9.0 kg (Charles River BRF, Inc.). All animals studied demonstrated a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract. Animals were housed individually in environmentally controlled rooms in open mesh cages and provided food twice daily and water ad libitum. Each animal was fasted for approximately 12 hours prior to the day of study.
  • ketamine hydrochloride 7 mg/kg, i.m.; Ketaset, Fort Dodge, Iowa
  • xylazine 1.2 mg/kg, i.m.; Bayer Corp., Elkart, Ind.
  • Ketamine 5 mg/kg, i.m. was used to supplement anesthesia as needed.
  • Airway responsiveness (AR) to inhaled methachroline followed by bronchoalveolar lavage (BAL) to assess airway cellular composition (ACC) were determined 3 days before (day 0) and 3 days after (day 10) three alternate-day (days 3,5,7) inhalations of Ascaris suum extract. Animals were rested 6 to 8 weeks between studies to allow airway responsiveness and inflammation to return to baseline (pre-antigen) levels. Treatment studies were bracketed by vehicle control studies to assure that no changes in sensitivity to antigen occurred over time.
  • test compounds dissolved in Ethanol:PEG400:Water (10:50:40 v/v) were administered under light anesthetisia
  • Rhs Respiratory System Resistance
  • the animal was connected to a Harvard Ventilator (Harvard Apparatus, S. Natick, Mass.) via the endotracheal tube and ventilated at a rate between 30-35 breaths per minute.
  • Airflow was measured by a Fleisch (Hans Rudolph) pneumotachograph and thoracic pressure was measured by a validyne pressure transducer (as the difference between the pressure at the distal end of the endotracheal tube and room pressure).
  • the pneumotachograph and validyne were connected to a pre-amplifier and then into an MI 2 respiratory analyzer (Malvern, Pa.). Using the primary signals of flow and pressure the analyzer computed airway resistance and compliance (as well as a number of other respiratory parameters).
  • Methacholine Dose Response Determinations To assess airway responsiveness to inhaled methacholine, cumulative dose response curves were constructed by administering increasing concentrations of methacholine until increases in Rrs of between 100 and 200% were obtained. A vehicle control challenge was performed prior to the first dose of methacholine. Changes in Rrs were measured continuously over a 10 minute period post aerosol challenge. Aerosol challenges were separated by 5 to 10 minutes or until Rrs returned to baseline values.
  • PC 100 Values The resistance obtained with PBS was set as zero. The percentage increase in resistance above zero at each dose of methacholine was entered into the computer and the program used an algorithm to determine the exact methacholine concentration which caused an increase in resistance of 100% above baseline (PC 100 ). Differences (day 10-day 0) in PC 100 values were calculated as logs (base 10) to normalize the data and account for the large variation in absolute values for the PC 100 between animals.
  • BAL was performed on alternating right and left lungs. Total white cells per milliliter of BAL fluid was obtained using a Coulter counter (Coulter Corp., Miami, Fla.). BAL cell composition was determined by counting a minimum of 200 cells from a Wright's stained cytospin slide preparation.
  • Blood Samples Blood samples were collected prior to and 30 minutes, 1 hr and 2 hr after the first dose of the test compounds (morning of day 2), immediately before each subsequent dose, and 30 minutes, 1 hr and 2 hr after the final dose (evening of day 9). Blood was collected from the femoral vein into EDTA, centrifuged at 1500 rpm for 15 minutes at 4° C. and the plasma stored at ⁇ 70° C. until assayed for the test compounds.
  • the compounds of the present invention also show more than 100-fold selectivity against CCR1, CCR5, CCR7. CCR8 and CXCR1 in receptor binding assays.
  • the compounds of the present invention show dose-dependent inhibitory effect on eotaxin-induced chemotaxis of human eosinophils and strong activity in vivo assays.
  • Example 1-1 or 1-2 In the similar manner as described in Example 1-1 or 1-2 above, compounds in Example 1-3 to 1-100 as shown in Table 1 were synthesized.
  • Example 2-2 to 2-24 as shown in Table 2 were synthesized.
  • Example 3-1 In the similar manner as described in Example 3-1 above, compounds in Example 3-2 to 3-12 as shown in Table 3 were synthesized.
  • Example 5-3 to 5-8 as shown in Table 5 were synthesized.
  • Example 6-1 or 6-2 In the similar manner as described in Example 6-1 or 6-2 above, compounds in Example 6-3, 6-4 and 6-5 as shown in Table 6 were synthesized.
  • Example 7-2 compounds in Example 7-2 to 7-9 as shown in Table 7 were synthesized.
  • Example 10-2 in the similar manner as described in Example 10-1 above, compound in Example 10-2 as shown in Table 10 was synthesized.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1-1 100 mg of the compound of Example 1-1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
  • the mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kN.
  • Example 1-1 1000 mg of the compound of Example 1-1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pa., USA) and 99 g of water.
  • a single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol and the active component is added to the suspension.
  • the water is added with stirring. Stirring is continued for about 6 h until the swelling of the Rhodigel is complete.

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090286771A1 (en) * 2003-03-24 2009-11-19 Yingfu Li 2-Phenoxy- and 2-Phenylsulfonamide Derivatives with CCR3 Antagonistic Activity for the Treatment of Inflammatory or Immunological Disorders
US20100204213A1 (en) * 2001-09-07 2010-08-12 Yingfu Li Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
US20100273785A1 (en) * 2009-04-22 2010-10-28 Tai Wei Ly 2,5-disubstituted arylsulfonamide ccr3 antagonists
US20100273782A1 (en) * 2009-04-22 2010-10-28 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide ccr3 antagonists
US20110218207A1 (en) * 2010-03-02 2011-09-08 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide ccr3 antagonists
US20110230487A1 (en) * 2010-03-17 2011-09-22 Tai Wei Ly Arylsulfonamide ccr3 antagonists
US8420639B2 (en) 2009-04-22 2013-04-16 Axikin Pharmaceuticals, Inc. Arylsulfonamide CCR3 antagonists
US9156799B2 (en) 2012-09-07 2015-10-13 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide CCR3 antagonists

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0200843D0 (sv) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
SE0203754D0 (sv) * 2002-12-17 2002-12-17 Astrazeneca Ab New compounds
AU2012238285B2 (en) * 2003-03-24 2015-07-02 Axikin Pharmaceuticals, Inc. Benzenesulfonamide derivatives
SE0300957D0 (sv) 2003-04-01 2003-04-01 Astrazeneca Ab Chemical compounds
TW200630337A (en) 2004-10-14 2006-09-01 Euro Celtique Sa Piperidinyl compounds and the use thereof
EP2402316A1 (en) 2005-07-21 2012-01-04 AstraZeneca AB (Publ) Piperidine derivatives
US8247442B2 (en) 2006-03-29 2012-08-21 Purdue Pharma L.P. Benzenesulfonamide compounds and their use
TW200812963A (en) 2006-04-13 2008-03-16 Euro Celtique Sa Benzenesulfonamide compounds and the use thereof
TW200815353A (en) 2006-04-13 2008-04-01 Euro Celtique Sa Benzenesulfonamide compounds and their use
BRPI0710512A2 (pt) 2006-04-20 2012-06-05 Hoffmann La Roche moduladores derivados de diazepan de receptores de quimiocinas
US8399486B2 (en) 2007-04-09 2013-03-19 Purdue Pharma L.P. Benzenesulfonyl compounds and the use thereof
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
WO2009040659A2 (en) 2007-09-28 2009-04-02 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
GEP20135992B (en) * 2009-01-12 2013-12-25 Icagen Inc Sulfonamide derivatives
TW201036941A (en) * 2009-03-30 2010-10-16 Sumitomo Chemical Co Method for producing sulfonamide compound
JP5756457B2 (ja) 2009-04-06 2015-07-29 アジオス ファーマシューティカルズ， インコーポレイテッド ピルビン酸キナーゼｍ２調節剤、治療組成物および関連する使用方法
WO2010129351A1 (en) 2009-04-28 2010-11-11 Schepens Eye Research Institute Method to identify and treat age-related macular degeneration
JP5764555B2 (ja) * 2009-06-29 2015-08-19 アジオス ファーマシューティカルズ， インコーポレイテッド 治療組成物および関連する使用方法
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CA2803118C (en) 2010-07-09 2015-11-03 Pfizer Limited Sulfonamide derivatives as nav 1.7 inhibitors
EP2627635A1 (en) * 2010-10-11 2013-08-21 Axikin Pharmaceuticals, Inc. Salts of arylsulfonamide ccr3 antagonists
ES2564952T3 (es) 2010-12-17 2016-03-30 Agios Pharmaceuticals, Inc. Nuevos derivados de N-(4-(azetidina-1-carbonil)fenil)-(hetero-)arilsulfonamida como moduladores de piruvato quinasa M2 (PKM2)
MX336022B (es) 2010-12-21 2016-01-06 Agios Pharmaceuticals Inc Activadores de pkm2 bicíclicos.
TWI549947B (zh) 2010-12-29 2016-09-21 阿吉歐斯製藥公司 治療化合物及組成物
SI2704721T1 (en) 2011-05-03 2018-08-31 Agios Pharmaceuticals, Inc. ACTIVATORS PIANO KINASE FOR USE IN THERAPY
US9181231B2 (en) 2011-05-03 2015-11-10 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia
WO2014139144A1 (en) 2013-03-15 2014-09-18 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
AU2016276951B2 (en) 2015-06-11 2020-10-08 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2275354A (en) 1937-11-29 1942-03-03 May & Baker Ltd Preparation of new therapeutically useful heterocyclic compounds
US3819639A (en) 1970-11-11 1974-06-25 Christiaens Sa A 2-metatrifluoromethylanilino-pyridine-5-n-acetyl sulfonamide
WO1999055324A1 (en) 1998-04-27 1999-11-04 Smithkline Beecham Corporation Ccr-3 receptor antagonists
WO2000042003A1 (en) 1999-01-13 2000-07-20 Warner-Lambert Company Benzenesulfonamide derivatives and their use as mek inhibitors
US6153757A (en) * 1995-12-08 2000-11-28 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors and intermediates useful for their preparation
WO2000076514A1 (en) 1999-06-11 2000-12-21 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
WO2000076513A1 (en) 1999-06-11 2000-12-21 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
WO2001032604A1 (en) 1999-11-05 2001-05-10 University College London Activators of soluble guanylate cyclase
WO2003022277A1 (en) 2001-09-07 2003-03-20 Bayer Healthcare Ag Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
US7173025B1 (en) * 1996-02-02 2007-02-06 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4233409A (en) 1979-07-05 1980-11-11 Monsanto Company Polymeric blend
WO1989005836A1 (en) 1987-12-14 1989-06-29 The Dow Chemical Company Abs compositions having trimodal rubber particle distributions
US5041498A (en) 1990-01-02 1991-08-20 The Dow Chemical Company Trimodal ABS compositions having good gloss and reduced gloss sensitivity
DE4404749A1 (de) 1994-02-15 1995-08-17 Bayer Ag ABS-Polymer-Zusammensetzungen mit gleichmäßiger matter Oberfläche
US6057322A (en) * 1995-01-30 2000-05-02 Hoechst Aktiengesellschaft Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic agent, and a medicament containing them
DE19507749A1 (de) 1995-03-06 1996-09-12 Bayer Ag Thermoplastische Formmassen vom ABS-Typ
DE19518025A1 (de) 1995-05-17 1996-11-21 Bayer Ag Thermoplastische ABS-Formmassen
US6262113B1 (en) * 1996-03-20 2001-07-17 Smithkline Beecham Corporation IL-8 receptor antagonists
DE19649249A1 (de) 1996-11-28 1998-06-04 Bayer Ag Verbesserte thermoplastische Formmassen vom ABS-Typ
US6284923B1 (en) * 1997-08-22 2001-09-04 Tularik Inc Substituted benzene compounds as antiproliferative and cholesterol lowering action
DE10008419A1 (de) 2000-02-23 2001-08-30 Bayer Ag Polymerzusammensetzungen mit verbesserter Eigenschaftskonstanz
DE10008420A1 (de) 2000-02-23 2001-08-30 Bayer Ag Polymerzusammensetzungen mit verbesserter Eigenschaftskonstanz
DE10145773A1 (de) 2001-09-17 2003-04-03 Bayer Ag ABS-Zusammensetzungen mit verbesserten Eigenschaftskombinationen
AU2004224807A1 (en) 2003-03-24 2004-10-07 Axikin Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfomamide derivatives with CCR3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2275354A (en) 1937-11-29 1942-03-03 May & Baker Ltd Preparation of new therapeutically useful heterocyclic compounds
US3819639A (en) 1970-11-11 1974-06-25 Christiaens Sa A 2-metatrifluoromethylanilino-pyridine-5-n-acetyl sulfonamide
US6153757A (en) * 1995-12-08 2000-11-28 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors and intermediates useful for their preparation
US7173025B1 (en) * 1996-02-02 2007-02-06 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
WO1999055324A1 (en) 1998-04-27 1999-11-04 Smithkline Beecham Corporation Ccr-3 receptor antagonists
WO2000042003A1 (en) 1999-01-13 2000-07-20 Warner-Lambert Company Benzenesulfonamide derivatives and their use as mek inhibitors
WO2000076514A1 (en) 1999-06-11 2000-12-21 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
WO2000076513A1 (en) 1999-06-11 2000-12-21 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
WO2001032604A1 (en) 1999-11-05 2001-05-10 University College London Activators of soluble guanylate cyclase
WO2003022277A1 (en) 2001-09-07 2003-03-20 Bayer Healthcare Ag Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
US20050070582A1 (en) 2001-09-07 2005-03-31 Bayer Healthcare Ag Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders

Non-Patent Citations (66)

* Cited by examiner, † Cited by third party
Title
"Chemokine CCR3 Antagonists," Exp. Opin. Ther. Patents, 2000, vol. 10(9), pp. 1455-1459.
"NAEP's asthma bulletin board," http://www.asthma.co.za/news01.htm, accessed Aug. 5, 2008.
Alaaeddine et al., "Production of the Chemokine RANTES by Articular Chrondrocytes and Role in Cartilage Degradation," Arthritis & Rheumatism, vol. 44, No. 7, pp. 1633-1643 (2001).
Ancuta et al., CD16+ monocyte-derived macrophages activate resting T cells for HIV infection by producing CCR3 and CCR4 ligands, J. Immunol., vol. 176, pp. 5760-5771 (2006).
Aust et al., "Grave's disease is associated with an altered CXCR3 and CCR5 expression in thyroid-derived compared to peripheral blood lymphocytes," Clin. Exp. Immunol., vol. 127, pp. 479-485 (2001).
Bertrand et al. "CCR3 Blockade as a new therapy for asthma," Expert Opinion on Investigational Drugs 9(1):4352 (2000).
Bertrand et al. "CCR3 Blockade as a new therapy for asthma," Expert Opinion on Investigational Drugs 9(1):4352 (2000).
Bhattacharya, et al., "Increased expression of eotaxin-3 distinguishes between eosinophilic esophagitis and gastroesophageal reflux disease," Human Pathology, vol. 38, pp. 1744-1753 (2007).
Blanchard et al., "Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis," J. Clin. Invest., vol. 116, No. 2, pp. 536-547 (2006).
Brauniger et al., Reactions with 2,4-dinitrofluorobenzene, especially with aromatic amines. I. Reaction conditions and synthetic compounds, Pharmazie, 12, 335-48 (1957). *
Bullock et al., "Interplay of adaptive Th2 immunity with eotaxin-3/C-C chemokine receptor 3 in eosinophilic esophagitis," J. Pediatric Gastroenterology and Nutrition, vol. 45, pp. 22-31 (2007).
Cheadle et al., "Eotaxin-2 and colorectal cancer: a potential target for immune therapy," Human Cancer Biol., vol. 13, No. 19, pp. 5719-5728 (2007).
Chemcats Database, Ambinter Stock Screening Collection, Order Nos. 7J-012, 7J-005 and 7J-004 (published Jan. 1, 2004).
Chemcats Database, Ambinter Stock Screening Collection, Order Nos. 7J-012, 7J-005 and 7J-004.
Chi et al., "C-Reactive protein enhances expression of chemokine receptors on mast cells," The FASEB Journal, vol. 16, No. 4, p. A690, abstract 514.2 (2002).
Dol et al., "Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice," J. Cardiovascular Pharmacolology, vol. 38, pp. 395-405 (2001).
Elsner et al., "Human Eotaxin Represents a Potential Activator of the Respiratory Burst of Human Eosinophils," Eur. J. Immunol., vol. 26, pp. 1919-1925 (1996).
Elsner et al., "Human Eotaxin Represents a Potential Activator of the Respiratory Burst of Human Eosinophils," Eur. J. Immunol., vol. 26, pp. 1919-1925 (1996).
Foster et al., "Elemental signals regulating eosinophil accumulation in the lung," Immunol. Rev., vol. 179, pp. 173-181 (2001).
Gerber et al., "Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils," Current Biology, vol. 7, pp. 836-843 (1997).
Haley et al., "Overexpression of Eotaxin and the CCR3 Receptor in Human Atherosclerosis: Using Genomic Technology to Identify a Potential Novel Pathway of Vascular Inflammation," Circulation, vol. 102, pp. 2185-2189 (2000).
Hogoboam et al., "Collagen Deposition in Non-Fibrotic Lung Granuloma Model after Nitric Oxide Inhibition," Am. J. Pathology, vol. 153, No. 6, pp. 1861-1872 (1998).
Hsu et al., "Production of the chemokine eotaxin-1 in osteoarthritis and its role in cartilage degradation," J. Cellular Biochem., vol. 93, pp. 929-939 (2004).
Huaux et al., "Role of eotaxin-1 (CCL11) and CC chemokine receptor 3 (CCR3) in bleomycin-induced lung injury and fibrosis," vol. 167, No. 6, pp. 1485-1496 (2005).
Hunt et al., "Newly identified genetic risk variants for celiac disease related to the immune response," Nature Genetics, vol. 40, No. 4, pp. 395-402 (2008).
International Search Report of International Application No. PCT/EP02/09873 having a Publication No. WO 03/022277 (published Mar. 20, 2003).
International Search Report of International Application No. PCT/EP02/09873 having a Publication No. WO 03/022277.
International Search Report of International Application No. PCT/EP2004/002496 having a Publication No. WO 2004/084898.
J. Delarge, "Nouveaux Anti-inflammatoires Derives de la Pyridine," Ann. Pharm. Fr., 1973, vol. 31, No. 6, pp. 467-474. (English summary at p. 474).
Jahnz-Royk et al., "Eotaxin in serum of patients with asthma or chronic obstructive pulmonary disease: relationship with eosophil cationic protein and lung function," Mediators of Inflam., vol. 9, pp. 175-179 (2000).
Johrer et al., "Up-regulation of functional chemokine receptor CCR3 in human renal cell carcinoma," Human Cancer Biol., vol. 11, No. 7, pp. 2459-2465 (2005).
Joubert et al., "CCR3 expression and function in asthmatic airway smooth muscle cells," J. Immunol., vol. 175, pp. 2702-2708 (2005).
Katschke et al., "Differential Expression of Chemokine Receptors on Peripheral Blood, Synovial Fluid, and Synovial Tissue Monocytes/Macrophages in Rheumatoid Arthritis," Arthritis & Rheumatism, vol. 44, No. 5, pp. 1022-1032 (2001).
Kouno et al. "Up-regulation of CC chemokine, CCL3L1, and receptors, CCR3, CCR5 in human glioblastoma that promotes cell growth," J. Neuro-Oncology, vol. 70, pp. 301-307 (2004).
Lamkhioued et al., "Increased expression of eotaxin in bronchoaveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation," J. Immunol., vol. 159, pp. 4593-4601 (1997).
Li et al., "Mast Cells/Basophils in the Peripheral Blood of Allergic Individuals Who Are HIV-1 Susceptible Due to Their Surface Expression of CD4 and the Chemokine Receptors CCR3, CCR5 and CXCR4," Blood, vol. 97, No. 11, pp. 3484-3487 (2001).
Marone et al., "Are Mast Cells MASTers in HIV-1 Infection?, " Int. Arch. Allergy Immunol., vol. 125, pp. 89-95 (2001).
Marone et al., "Human Mast Cells and Basophils in HIV-1 Infection," Trends Immunol., vol. 22, No. 5., 229-232 (2001).
Mastrukova et al., "The Application of the Hammett Equation to the Theory of Tautomeric Equilibrium-II," Tetrahedron, 1963, vol. 19, pp. 357-372.
Matsukura et al., "Expression of RANTES by normal airway epithelial cells after influenza virus A infection," Am. J. Respir. Cell and Mol. Biol., vol. 18, pp. 255-264 (1998).
Nissinen et al., "CCR3, CCR5 interleukin 4, and interferon-gamma expression on synovial and peripheral T cells and monocytes in rheumatoid arthritis," J. Rheumatol., vol. 30, No. 9, pp. 1928-1934 (2003).
Office Action dated Aug. 19, 2008 in U.S. Appl. No. 10/550,482.
Ohagen et al., "Genetic and functional analysis of full-length human immunodeficiency virus type 1 env genes derived from brain and blood or patients with AIDS," J. Virology, vol. 77, No. 22, pp. 12336-12345. (2003).
Oliviera et al., "Stem cell factor and IgE-stimulated murine mast cells produce chemokines (CCL2, CCL17, CCL22) and express chemokine receptors," Inflamm. Res., vol. 50, pp. 168-174 (2001).
Park et al., "CD4 Receptor-Dependent Entry of Human Immunodeficiency Virus Type-I env-Pseudotypes into CCR5-, CCR3- and CXCR4-Expressing Human Alveolar Macrophages Is Preferrentially Mediated by the CCR5 Coreceptor," Am. J. Respir. Cell Mol. Biol., vol. 20, pp. 864-871 (1999).
Ponath, P. "Chemokine receptor antagonists: novel therapeutics for inflammation and AIDS," Expert Opinion on Investigational Drugs 7(1): 1-18 (1998).
Rothenberg et al., "Targeted Disruption of the Chemokine Eotaxin Partially Reduces Antigen-induced Tissue Eosophilia," J. Exp. Med., vol. 185, pp. 785-790 (1997).
Ruth et al., "Expression and Participation of Eotaxin During Mycobacterial (Type 1) and Schistosomal (Type 2) Antigen-Elicited Granuloma Formation," J. Immunology, vol. 161, No. 8, pp. 4276-4282 (1998).
Saari et al., "Synthesis and Evaluation of Some Nitrobenzenesulfonamides Containing Nitroisopropyl and (Ureidooxy)methyl Groups as Novel Hypoxic Cell Selective Cytotoxic Agents," J. Med. Chem. 1991, 34, 3132-3138.
Sabroe et al., J. Immunol., "Cloning and Characterization of the Guinea Pig Eosinophil Eotaxin Receptor, C-C Chemokine Receptor-3: Blockade Using a Monoclonal Antibody In Vivo," vol. 161, pp. 6139-6147 (1998).
Saito et al., "Selective regulation of chemokine production in human epithelial cells," J. Infect. Dis., vol. 175, pp. 479-504 (1997).
Sallusto et al., "Selective Expression of the Eotaxin Receptor CCR3 by Human T Helper 2 Cells," Science, vol. 277, pp. 2005-2007 (1997).
Silva et al., "Differential expression of chemokines and chemokine receptors in inflammatory periapical diseases," Oral Microbiol. Immunol., vol. 20, pp. 310-316 (2005).
Simchen et al. "Expression and Regulation of Regulated on Activation, Normal T Cells Expressed and Secreted in Thyroid Tissue of Patients with Graves' Disease and Thyroid Autonomy and in Thyroid-Derived Cell Populations," J. Clinical Endocrinology & Metabolism, vol. 85, No. 2, 4758-64 (2000).
Stellato et al.,"Cutting Edge: Expression of the C-C Chemokine Receptor CCR3 in Human Airway Epithelial Cells," J. Immunology, 1457-60 (2001).
Sugasawa et al., "Prognostic significance of expression of CCL5/RANTES receptors in patients with gastric cancer," J. Sergical Oncology. vol. 97, pp. 447-450 (2008).
Teixeira et al., "Increased serum levels of CCL11/eotaxin in schizophrenia," Progress in Neuro-pharmacology & Biol. Psych., vol. 32, pp. 710-714. (2008).
Uguccioni et al., "High Expression of the Chemokine Receptor CCR3 in Human Blood Basophils," J. Clin. Invest., vol. 100, pp. 1137-1143 (1997).
Weeraratna et al., "Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues," Exp. Cell. Res., vol. 313, pp. 450-461 (2007).
White et al., "Identification of potent, selective, non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration," J. Bio. Chem., vol. 275, No. 47, pp. 36626-36631 (2000).
White J R, et al., Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration, The Journal of biological chemistry, (Nov. 24, 2000) vol. 275, No. 47, pp. 36626-36631. *
Xia et al., "Chemokines/Chemokine Receptors in the Central Nervous System and Alzheimer's Disease," J. Neurovirology, vol. 5, pp. 32-41 (1999).
Xia et al., "Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer's disease," J. Immunol., 108, 227-35 (2000).
Xia et al., "Immunihistochemical Study of the beta Chemokine Receptors of CCR3 and CCR5 and Their Ligands in Normal and Alzheimer's Diseases Brains," Am. J. Pathology, vol. 153, No. 1, pp. 31-36 1998.
Xia et al., "Immunihistochemical Study of the β Chemokine Receptors of CCR3 and CCR5 and Their Ligands in Normal and Alzheimer's Diseases Brains," Am. J. Pathology, vol. 153, No. 1, pp. 31-36 1998.
Ying et al., "Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma. Association with airway hyperresponsiveness and predominant colocalization of eotaxin mRNA to bronchial epithelial and endothelial cells," Eur. J. Immunol, vol. 27, 3507-3516 (1997).

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